ProjectAction Selection under Contextual Uncertainty: the Role of Learning and Effective Connectivity in the Human Brain

Researcher (PI)Sven Bestmann

Host Institution (HI)UNIVERSITY COLLEGE LONDON

Call DetailsStarting Grant (StG), LS5, ERC-2010-StG_20091118

SummaryIn a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival.
This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection.
I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour.
My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging.
My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about.
If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.

In a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival.
This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection.
I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour.
My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging.
My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about.
If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.

Host Institution (HI)THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

Call DetailsStarting Grant (StG), LS5, ERC-2010-StG_20091118

SummaryWithin a 12 month period, 20% of adults will meet criteria for one or more clinical anxiety disorders (ADs). These disorders are hugely disruptive, placing an emotional burden on individuals and their families. While both cognitive behavioural therapy and pharmacological treatment are widely viewed as effective strategies for managing ADs, systematic review of the literature reveals that only 30–45% of patients demonstrate a marked response to treatment (anxiety levels being reduced into the nonaffected range). In addition, a significant proportion of initial responders relapse after treatment is discontinued. There is hence a real and marked need to improve upon current approaches to AD treatment.
One possible avenue for improving response rates is through optimizing initial treatment selection. Specifically, it is possible that certain individuals might respond better to cognitive interventions while others might respond better to pharmacological treatment. Recently it has been suggested that there may be two or more distinct biological pathways disrupted in anxiety. If this is the case, then specification of these pathways may be an important step in predicting which individuals are likely to respond to which treatment. Few studies have focused upon this issue and, in particular, upon identifying neural markers that might predict response to cognitive (as opposed to pharmacological) intervention. The proposed research aims to address this. Specifically, it tests the hypothesis that there are at least two mechanisms disrupted in ADs, one entailing amygdala hyper-responsivity to cues that signal threat, the other impoverished recruitment of frontal regions that support cognitive and emotional regulation.
Two series of functional magnetic resonance imaging experiments will be conducted. These will investigate differences in amygdala and frontal function during (a) attentional processing and (b) fear conditioning. Initial clinical experiments will investigate whether Generalised Anxiety Disorder and Specific Phobia involve differing degrees of disruption to frontal versus amygdala function during these tasks. This work will feed into training studies, the goal being to characterize AD patient subgroups that benefit from cognitive training.

Within a 12 month period, 20% of adults will meet criteria for one or more clinical anxiety disorders (ADs). These disorders are hugely disruptive, placing an emotional burden on individuals and their families. While both cognitive behavioural therapy and pharmacological treatment are widely viewed as effective strategies for managing ADs, systematic review of the literature reveals that only 30–45% of patients demonstrate a marked response to treatment (anxiety levels being reduced into the nonaffected range). In addition, a significant proportion of initial responders relapse after treatment is discontinued. There is hence a real and marked need to improve upon current approaches to AD treatment.
One possible avenue for improving response rates is through optimizing initial treatment selection. Specifically, it is possible that certain individuals might respond better to cognitive interventions while others might respond better to pharmacological treatment. Recently it has been suggested that there may be two or more distinct biological pathways disrupted in anxiety. If this is the case, then specification of these pathways may be an important step in predicting which individuals are likely to respond to which treatment. Few studies have focused upon this issue and, in particular, upon identifying neural markers that might predict response to cognitive (as opposed to pharmacological) intervention. The proposed research aims to address this. Specifically, it tests the hypothesis that there are at least two mechanisms disrupted in ADs, one entailing amygdala hyper-responsivity to cues that signal threat, the other impoverished recruitment of frontal regions that support cognitive and emotional regulation.
Two series of functional magnetic resonance imaging experiments will be conducted. These will investigate differences in amygdala and frontal function during (a) attentional processing and (b) fear conditioning. Initial clinical experiments will investigate whether Generalised Anxiety Disorder and Specific Phobia involve differing degrees of disruption to frontal versus amygdala function during these tasks. This work will feed into training studies, the goal being to characterize AD patient subgroups that benefit from cognitive training.

Max ERC Funding

1 708 407 €

Duration

Start date: 2011-04-01, End date: 2016-08-31

Project acronymAVIAN DIMORPHISM

ProjectThe genomic and transcriptomic locus of sex-specific selection in birds

Researcher (PI)Judith Elizabeth Mank

Host Institution (HI)UNIVERSITY COLLEGE LONDON

Call DetailsStarting Grant (StG), LS8, ERC-2010-StG_20091118

SummaryIt has long been understood that genes contribute to phenotypes that are then the basis of selection. However, the nature and process of this relationship remains largely theoretical, and the relative contribution of change in gene expression and coding sequence to phenotypic diversification is unclear. The aim of this proposal is to fuse information about sexually dimorphic phenotypes, the mating systems and sexually antagonistic selective agents that shape sexual dimorphism, and the sex-biased gene expression patterns that encode sexual dimorphisms, in order to create a cohesive integrated understanding of the relationship between evolution, the genome, and the animal form. The primary approach of this project is to harnesses emergent DNA sequencing technologies in order to measure evolutionary change in gene expression and coding sequence in response to different sex-specific selection regimes in a clade of birds with divergent mating systems. Sex-specific selection pressures arise in large part as a consequence of mating system, however males and females share nearly identical genomes, especially in the vertebrates where the sex chromosomes house very small proportions of the overall transcriptome. This single shared genome creates sex-specific phenotypes via different gene expression levels in females and males, and these sex-biased genes connect sexual dimorphisms, and the sexually antagonistic selection pressures that shape them, with the regions of the genome that encode them.
The Galloanserae (fowl and waterfowl) will be used to in the proposed project, as this clade combines the necessary requirements of both variation in mating systems and a well-conserved reference genome (chicken). The study species selected from within the Galloanserae for the proposal exhibit a range of sexual dimorphism and sperm competition, and this will be exploited with next generation (454 and Illumina) genomic and transcriptomic data to study the gene expression patterns that underlie sexual dimorphisms, and the evolutionary pressures acting on them. This work will be complemented by the development of mathematical models of sex-specific evolution that will be tested against the gene expression and gene sequence data in order to understand the mechanisms by which sex-specific selection regimes, arising largely from mating systems, shape the phenotype via the genome.

It has long been understood that genes contribute to phenotypes that are then the basis of selection. However, the nature and process of this relationship remains largely theoretical, and the relative contribution of change in gene expression and coding sequence to phenotypic diversification is unclear. The aim of this proposal is to fuse information about sexually dimorphic phenotypes, the mating systems and sexually antagonistic selective agents that shape sexual dimorphism, and the sex-biased gene expression patterns that encode sexual dimorphisms, in order to create a cohesive integrated understanding of the relationship between evolution, the genome, and the animal form. The primary approach of this project is to harnesses emergent DNA sequencing technologies in order to measure evolutionary change in gene expression and coding sequence in response to different sex-specific selection regimes in a clade of birds with divergent mating systems. Sex-specific selection pressures arise in large part as a consequence of mating system, however males and females share nearly identical genomes, especially in the vertebrates where the sex chromosomes house very small proportions of the overall transcriptome. This single shared genome creates sex-specific phenotypes via different gene expression levels in females and males, and these sex-biased genes connect sexual dimorphisms, and the sexually antagonistic selection pressures that shape them, with the regions of the genome that encode them.
The Galloanserae (fowl and waterfowl) will be used to in the proposed project, as this clade combines the necessary requirements of both variation in mating systems and a well-conserved reference genome (chicken). The study species selected from within the Galloanserae for the proposal exhibit a range of sexual dimorphism and sperm competition, and this will be exploited with next generation (454 and Illumina) genomic and transcriptomic data to study the gene expression patterns that underlie sexual dimorphisms, and the evolutionary pressures acting on them. This work will be complemented by the development of mathematical models of sex-specific evolution that will be tested against the gene expression and gene sequence data in order to understand the mechanisms by which sex-specific selection regimes, arising largely from mating systems, shape the phenotype via the genome.

SummaryEpidemiology and public health planning will increasingly rely on the analysis of genetic sequence data. The recent swine-derived influenza A/H1N1 pandemic may represent a tipping point in this trend, as it is arguably the first time when multiple strains of a human pathogen have been sequenced essentially in real time from the very beginning of its spread. However, the full potential of genetic information cannot be fully exploited to infer the spread of epidemics due to the lack of statistical methodologies capable of reconstructing transmission routes from genetic data structured both in time and space. To address this urgent need, we propose to develop a methodological framework for the reconstruction of the spatiotemporal dynamics of disease outbreaks and epidemics based on genetic sequence data. Rather than reconstructing most recent common ancestors as in phylogenetics, we will directly infer the most likely ancestries among the sampled isolates. This represents an entirely novel paradigm and allows for the development of statistically coherent and powerful inference software within a Bayesian framework. The methodological framework will be developed in parallel with the analysis of real genetic/genomic data from important human pathogens. We will in particular focus on the 2009 A/H1N1 pandemic influenza, methicilin-resistant Staphylococcus aureus clones (MRSAs), Batrachochytrium dendrobatidis, a fungus currently devastating amphibian populations worldwide. The tools we are proposing to develop are likely to impact radically on the field of infectious disease epidemiology and affect the way infectious emerging pathogens are monitored by biologists and public health professionals.

Epidemiology and public health planning will increasingly rely on the analysis of genetic sequence data. The recent swine-derived influenza A/H1N1 pandemic may represent a tipping point in this trend, as it is arguably the first time when multiple strains of a human pathogen have been sequenced essentially in real time from the very beginning of its spread. However, the full potential of genetic information cannot be fully exploited to infer the spread of epidemics due to the lack of statistical methodologies capable of reconstructing transmission routes from genetic data structured both in time and space. To address this urgent need, we propose to develop a methodological framework for the reconstruction of the spatiotemporal dynamics of disease outbreaks and epidemics based on genetic sequence data. Rather than reconstructing most recent common ancestors as in phylogenetics, we will directly infer the most likely ancestries among the sampled isolates. This represents an entirely novel paradigm and allows for the development of statistically coherent and powerful inference software within a Bayesian framework. The methodological framework will be developed in parallel with the analysis of real genetic/genomic data from important human pathogens. We will in particular focus on the 2009 A/H1N1 pandemic influenza, methicilin-resistant Staphylococcus aureus clones (MRSAs), Batrachochytrium dendrobatidis, a fungus currently devastating amphibian populations worldwide. The tools we are proposing to develop are likely to impact radically on the field of infectious disease epidemiology and affect the way infectious emerging pathogens are monitored by biologists and public health professionals.

Max ERC Funding

1 483 080 €

Duration

Start date: 2010-11-01, End date: 2015-10-31

Project acronymBLUELEAF

ProjectThe adaptive advantages, evolution and development of iridescence in leaves

Researcher (PI)Heather Whitney

Host Institution (HI)UNIVERSITY OF BRISTOL

Call DetailsStarting Grant (StG), LS8, ERC-2010-StG_20091118

SummaryIridescence is a form of structural colour which changes hue according to the angle from which it is viewed. Blue iridescence caused by multilayers has been described on the leaves of taxonomically diverse species such as the lycophyte Selaginella uncinata and the angiosperm Begonia pavonina. While much is known about the role of leaf pigment colour, the adaptive role of leaf iridescence is unknown. Hypotheses have been put forward including 1) iridescence acts as disruptive camouflage against herbivores 2) it enhances light sensing and capture in low light conditions 3) it is a photoprotective mechanism to protect shade-adapted plants against high light levels. These hypotheses are not mutually exclusive: each function may be of varying importance in different environments. To understand any one function, we need a interdisciplinary approach considering all three potential functions and their interactions. The objective of my research would be to test these hypotheses, using animal behavioural and plant physiological methods, to determine the functions of leaf iridescence and how the plant has adapted to the reflection of developmentally vital wavelengths. Use of molecular and bioinformatics methods will elucidate the genes that control the production of this potentially multifunctional optical phenomenon. This research will provide a pioneering study into the generation, developmental impact and adaptive significance of iridescence in leaves. It would also answer questions at the frontiers of several fields including those of plant evolution, insect vision, methods of camouflage, the generation and role of animal iridescence, and could also potentially inspire synthetic biomimetic applications.

Iridescence is a form of structural colour which changes hue according to the angle from which it is viewed. Blue iridescence caused by multilayers has been described on the leaves of taxonomically diverse species such as the lycophyte Selaginella uncinata and the angiosperm Begonia pavonina. While much is known about the role of leaf pigment colour, the adaptive role of leaf iridescence is unknown. Hypotheses have been put forward including 1) iridescence acts as disruptive camouflage against herbivores 2) it enhances light sensing and capture in low light conditions 3) it is a photoprotective mechanism to protect shade-adapted plants against high light levels. These hypotheses are not mutually exclusive: each function may be of varying importance in different environments. To understand any one function, we need a interdisciplinary approach considering all three potential functions and their interactions. The objective of my research would be to test these hypotheses, using animal behavioural and plant physiological methods, to determine the functions of leaf iridescence and how the plant has adapted to the reflection of developmentally vital wavelengths. Use of molecular and bioinformatics methods will elucidate the genes that control the production of this potentially multifunctional optical phenomenon. This research will provide a pioneering study into the generation, developmental impact and adaptive significance of iridescence in leaves. It would also answer questions at the frontiers of several fields including those of plant evolution, insect vision, methods of camouflage, the generation and role of animal iridescence, and could also potentially inspire synthetic biomimetic applications.

Max ERC Funding

1 118 378 €

Duration

Start date: 2011-01-01, End date: 2016-07-31

Project acronymBrainNanoFlow

ProjectNanoscale dynamics in the extracellular space of the brain in vivo

Researcher (PI)Juan Alberto VARELA

Host Institution (HI)THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS

Call DetailsStarting Grant (StG), LS5, ERC-2018-STG

SummaryAggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.

Aggregates of proteins such as amyloid-beta and alpha-synuclein circulate the extracellular space of the brain (ECS) and are thought to be key players in the development of neurodegenerative diseases. The clearance of these aggregates (among other toxic metabolites) is a fundamental physiological feature of the brain which is poorly understood due to the lack of techniques to study the nanoscale organisation of the ECS. Exciting advances in this field have recently shown that clearance is enhanced during sleep due to a major volume change in the ECS, facilitating the flow of the interstitial fluid. However, this process has only been characterised at a low spatial resolution while the physiological changes occur at the nanoscale. The recently proposed “glymphatic” pathway still remains controversial, as there are no techniques capable of distinguishing between diffusion and bulk flow in the ECS of living animals. Understanding these processes at a higher spatial resolution requires the development of single-molecule imaging techniques that can study the brain in living animals. Taking advantage of the strategies I have recently developed to target single-molecules in the brain in vivo with nanoparticles, we will do “nanoscopy” in living animals. Our proposal will test the glymphatic pathway at the spatial scale in which events happen, and explore how sleep and wake cycles alter the ECS and the diffusion of receptors in neuronal plasma membrane. Overall, BrainNanoFlow aims to understand how nanoscale changes in the ECS facilitate clearance of protein aggregates. We will also provide new insights to the pathological consequences of impaired clearance, focusing on the interactions between these aggregates and their putative receptors. Being able to perform single-molecule studies in vivo in the brain will be a major breakthrough in neurobiology, making possible the study of physiological and pathological processes that cannot be studied in simpler brain preparations.

Max ERC Funding

1 552 948 €

Duration

Start date: 2018-12-01, End date: 2023-11-30

Project acronymCOEVOPRO

ProjectDrivers and consequences of coevolution in protective symbiosis

Researcher (PI)Kayla KING

Host Institution (HI)THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

Call DetailsStarting Grant (StG), LS8, ERC-2018-STG

SummaryAll organisms in nature are targets for parasite attack. Over a century ago, it was first observed that symbiotic species living in hosts can provide a strong barrier against infection, beyond the host’s own defence responses. We now know that ‘protective’ microbial symbiont species are key components of plant, animal, and human microbiota, shaping host health in the face of parasite infection. I have shown that microbes can evolve within days to protect, providing the possibility that microbe-mediated defences can take-over from hosts in fighting with parasites over evolutionary time. This new discovery of an evolvable microbe-mediated defence challenges our fundamental understanding of the host-parasite relationship. Here, I will use a novel nematode-microbe interaction, an experimental evolution approach, and assays of phenotypic and genomic changes (the latter using state-of-the-art sequencing and CRISPR-Cas9 technologies) to generate new insights into the drivers and consequences of coevolving protective symbioses. Specifically, the objectives are to test: (i) the ability of microbe-mediated protection to evolve more rapidly than host-encoded resistance, (ii) the impacts of evolvable protective microbes on host-parasite coevolution, and the effect of community complexity, in the form of (iii) parasite and (iv) within-host microbial heterogeneity, in shaping host-protective microbe coevolution from scratch. Together, these objectives will generate a new, synthetic understanding of how protective symbioses evolve and influence host resistance and parasite infectivity, with far-reaching implications for tackling coevolution in communities.

All organisms in nature are targets for parasite attack. Over a century ago, it was first observed that symbiotic species living in hosts can provide a strong barrier against infection, beyond the host’s own defence responses. We now know that ‘protective’ microbial symbiont species are key components of plant, animal, and human microbiota, shaping host health in the face of parasite infection. I have shown that microbes can evolve within days to protect, providing the possibility that microbe-mediated defences can take-over from hosts in fighting with parasites over evolutionary time. This new discovery of an evolvable microbe-mediated defence challenges our fundamental understanding of the host-parasite relationship. Here, I will use a novel nematode-microbe interaction, an experimental evolution approach, and assays of phenotypic and genomic changes (the latter using state-of-the-art sequencing and CRISPR-Cas9 technologies) to generate new insights into the drivers and consequences of coevolving protective symbioses. Specifically, the objectives are to test: (i) the ability of microbe-mediated protection to evolve more rapidly than host-encoded resistance, (ii) the impacts of evolvable protective microbes on host-parasite coevolution, and the effect of community complexity, in the form of (iii) parasite and (iv) within-host microbial heterogeneity, in shaping host-protective microbe coevolution from scratch. Together, these objectives will generate a new, synthetic understanding of how protective symbioses evolve and influence host resistance and parasite infectivity, with far-reaching implications for tackling coevolution in communities.

Max ERC Funding

1 499 275 €

Duration

Start date: 2019-02-01, End date: 2024-01-31

Project acronymCOMPLEXI&AGING

ProjectModulation of mitochondrial complex I as a strategy to increase lifespan and prevent age-related diseases

Researcher (PI)Alberto Sanz Montero

Host Institution (HI)UNIVERSITY OF NEWCASTLE UPON TYNE

Call DetailsStarting Grant (StG), LS4, ERC-2010-StG_20091118

SummaryNowadays, ageing is one of the main problems in Western society. The increase in the percentage of elderly people serves to strain the Social Security to the point of bankruptcy. The only way to alleviate the suffering caused by age-related degenerative disease is to fully understand the underlying forces which drive ageing and design strategies to delay it. Mitochondria are considered as central modulators of longevity in different species. It has been proposed that free radicals cause the accumulation of oxidative damage and as a result ageing. In accordance with this, production of Reactive Oxygen Species (ROS) by complex I negatively correlates with longevity. However, the overexpression of antioxidants or the reduction of ROS levels does not increase lifespan. These contradictory data can only be reconciled if complex I is modulating longevity through a ROS independent mechanism. We have expressed the alternative internal NADH dehydrogenase 1 (NDI1) from Saccharomyces cerevisiae in Drosophila melanogaster. The expression of NDI1 does not change the level of ROS but increases both the ratio of NAD+/NADH and Drosophila longevity. The main objective of this proposal is to study the mechanisms by which complex I regulates longevity. My general hypothesis is that complex I regulates longevity through a ROS independent mechanism. I propose that complex I controls the cellular levels of NAD+/NADH, keeping their levels at an equilibrium that favours the optimal functioning of the cell. When the ratio is moved towards NADH ageing is promoted, whereas when it is moved towards NAD+ pro-survival pathways are activated. I proposed two specific mechanisms downstream of complex I that promote cellular longevity or senescence: 1) activation of sirtuins, which would increase genome stability and 2) reduction of methylglyoxal generation, which would decrease the accumulation of cellular garbarge .

Nowadays, ageing is one of the main problems in Western society. The increase in the percentage of elderly people serves to strain the Social Security to the point of bankruptcy. The only way to alleviate the suffering caused by age-related degenerative disease is to fully understand the underlying forces which drive ageing and design strategies to delay it. Mitochondria are considered as central modulators of longevity in different species. It has been proposed that free radicals cause the accumulation of oxidative damage and as a result ageing. In accordance with this, production of Reactive Oxygen Species (ROS) by complex I negatively correlates with longevity. However, the overexpression of antioxidants or the reduction of ROS levels does not increase lifespan. These contradictory data can only be reconciled if complex I is modulating longevity through a ROS independent mechanism. We have expressed the alternative internal NADH dehydrogenase 1 (NDI1) from Saccharomyces cerevisiae in Drosophila melanogaster. The expression of NDI1 does not change the level of ROS but increases both the ratio of NAD+/NADH and Drosophila longevity. The main objective of this proposal is to study the mechanisms by which complex I regulates longevity. My general hypothesis is that complex I regulates longevity through a ROS independent mechanism. I propose that complex I controls the cellular levels of NAD+/NADH, keeping their levels at an equilibrium that favours the optimal functioning of the cell. When the ratio is moved towards NADH ageing is promoted, whereas when it is moved towards NAD+ pro-survival pathways are activated. I proposed two specific mechanisms downstream of complex I that promote cellular longevity or senescence: 1) activation of sirtuins, which would increase genome stability and 2) reduction of methylglyoxal generation, which would decrease the accumulation of cellular garbarge .

Max ERC Funding

1 491 600 €

Duration

Start date: 2011-02-01, End date: 2016-09-30

Project acronymDISEASE

ProjectDisease Risk And Immune Strategies In Social Insects

Researcher (PI)Nathalie STROEYMEYT

Host Institution (HI)UNIVERSITY OF BRISTOL

Call DetailsStarting Grant (StG), LS8, ERC-2018-STG

SummaryGroup-living has been predicted to have opposing effects on disease risk and immune strategies. First, since repeated contacts between individuals facilitate pathogen transmission, sociality may favour high investment in personal immunity. Alternatively, because social animals can limit disease spread through collective sanitary actions (e.g., mutual grooming) or organisational features (e.g., division of the group’s social network into distinct subsets), sociality may instead favour low investment in personal immunity. The overall goal of this project is to experimentally test these conflicting predictions in ants using advanced data collection and analytical tools. I will first quantify the effect of social organisation on disease transmission using a combination of automated behavioural tracking, social network analysis, and empirical tracking of transmission markers (fluorescent beads). Experimental network manipulations and controlled disease seeding by a robotic ant will allow key predictions from network epidemiology to be tested, with broad implications for disease management strategies. I will then study the effect of colony size on social network structure and disease transmission, and how this in turn affects investment in personal immunity. This will shed light on far-reaching hypotheses about the effect of group size on social organisation ('size-complexity’ hypothesis) and immune investment (‘density-dependent prophylaxis’). Finally, I will explore whether prolonged pathogen pressure induces colonies to reinforce the transmission-inhibiting aspects of their social organisation (e.g., colony fragmentation) or to invest more in personal immunity. This project will represent the first empirical investigation of the role of social organisation in disease risk management, and allow its importance to be compared with other immune strategies. This will constitute a significant advance in our understanding of the complex feedback between sociality and health.

Group-living has been predicted to have opposing effects on disease risk and immune strategies. First, since repeated contacts between individuals facilitate pathogen transmission, sociality may favour high investment in personal immunity. Alternatively, because social animals can limit disease spread through collective sanitary actions (e.g., mutual grooming) or organisational features (e.g., division of the group’s social network into distinct subsets), sociality may instead favour low investment in personal immunity. The overall goal of this project is to experimentally test these conflicting predictions in ants using advanced data collection and analytical tools. I will first quantify the effect of social organisation on disease transmission using a combination of automated behavioural tracking, social network analysis, and empirical tracking of transmission markers (fluorescent beads). Experimental network manipulations and controlled disease seeding by a robotic ant will allow key predictions from network epidemiology to be tested, with broad implications for disease management strategies. I will then study the effect of colony size on social network structure and disease transmission, and how this in turn affects investment in personal immunity. This will shed light on far-reaching hypotheses about the effect of group size on social organisation ('size-complexity’ hypothesis) and immune investment (‘density-dependent prophylaxis’). Finally, I will explore whether prolonged pathogen pressure induces colonies to reinforce the transmission-inhibiting aspects of their social organisation (e.g., colony fragmentation) or to invest more in personal immunity. This project will represent the first empirical investigation of the role of social organisation in disease risk management, and allow its importance to be compared with other immune strategies. This will constitute a significant advance in our understanding of the complex feedback between sociality and health.

Max ERC Funding

1 499 995 €

Duration

Start date: 2019-04-01, End date: 2024-03-31

Project acronymECONENDLIFE

ProjectThe economic evaluation of end of life care

Researcher (PI)Joanna Coast

Host Institution (HI)THE UNIVERSITY OF BIRMINGHAM

Call DetailsStarting Grant (StG), LS7, ERC-2010-StG_20091118

SummaryMaking choices about the health care that we provide in society is a fundamental and unavoidable issue. Economic evaluation aids this decision-making by supplying information about costs and benefits of different interventions. For end of life care, however, current evaluative frameworks are inadequate because they focus only on health and only on the patient. Amartya Sen’s capability approach offers an alternative and appropriate framework for evaluating end of life care and this programme aims to build on my ground-breaking work in the application of Sen’s approach to measurement within economic evaluation. Six key tasks will be undertaken: (i) defining the ‘end of life’ period using semi-structured interviews with key stakeholders; (ii) assessing the construct validity and sensitivity to change of a descriptive system for evaluating capabilities related to end of life care; (iii) eliciting values for this descriptive system from the general public and patients at the end of life using the best-worst scaling technique; (iv) developing a descriptive system to evaluate the impact on families’ capabilities of end of life care, using in-depth interviews to develop conceptual attributes; (v) conducting exploratory theoretical and methodological work on weighting across measures; and (vi) exploring views of the public and key stakeholders about appropriate decision-rules for end of life care, using a combination of focus groups and in-depth interviews. The work involves frontier research at the interface between health, economics and human development. It will address the significant methodological issues associated with the economic evaluation of end of life care and so advance the state-of-the-art to a point where robust economic evaluation of end of life care is feasible.

Making choices about the health care that we provide in society is a fundamental and unavoidable issue. Economic evaluation aids this decision-making by supplying information about costs and benefits of different interventions. For end of life care, however, current evaluative frameworks are inadequate because they focus only on health and only on the patient. Amartya Sen’s capability approach offers an alternative and appropriate framework for evaluating end of life care and this programme aims to build on my ground-breaking work in the application of Sen’s approach to measurement within economic evaluation. Six key tasks will be undertaken: (i) defining the ‘end of life’ period using semi-structured interviews with key stakeholders; (ii) assessing the construct validity and sensitivity to change of a descriptive system for evaluating capabilities related to end of life care; (iii) eliciting values for this descriptive system from the general public and patients at the end of life using the best-worst scaling technique; (iv) developing a descriptive system to evaluate the impact on families’ capabilities of end of life care, using in-depth interviews to develop conceptual attributes; (v) conducting exploratory theoretical and methodological work on weighting across measures; and (vi) exploring views of the public and key stakeholders about appropriate decision-rules for end of life care, using a combination of focus groups and in-depth interviews. The work involves frontier research at the interface between health, economics and human development. It will address the significant methodological issues associated with the economic evaluation of end of life care and so advance the state-of-the-art to a point where robust economic evaluation of end of life care is feasible.